We propose to investigate the metabolism of cyclic nucleotides in cone visual cells of the 13-line ground squirrel and in diseased cones of the Alaskan malamute dog that is affected by an inherited retinal degeneration. Metabolism will be assessed by measuring the content of cAMP and cGMP, and the activity of the corresponding synthetic and degradative enzymes. Kinetic characteristics and mechanisms for activation or inhibition of the respective cyclases or phosphodiesterases will be studied. A link between cyclic nucleotide metabolism and visual pigment bleaching will be explored by measuring whether light produces an alteration in cyclic nucleotide levels of cone visual cells. Modulation of cone metabolism by cyclic nucleotides may occur through the controlled phosphorylation of specific proteins and such a mechanism will be studied using isolated cone outer segments. This systemic study of cyclic nucleotide metabolism is designed to produce insights into the control of cone metabolism or function and to further our understanding of cone degeneration.